This invention relates to compositions that are easily spreadable onto and adhesive to biomembranes. They contain and provide moisture to the biomembranes and do not readily flow off, i.e., leak from, the biomembranes. Nor are they readily removed or washed from the biomembranes. Compositions that adhere to and are compatible with, in that they spread, and do not flow off and are not readily removed or washed from the biomembranes are deemed to be bioadhesive. Such compositions are particularly useful for maintaining biomembranes in a moist condition, for lubricating the biomembranes, and for providing a vehicle for containing and delivering medicaments, such as contraceptives, antifungals and antibacterials. The invention further relates to methods for making and methods of use of such compositions.
Polymers which have been known in the past for use in bioadhesive compositions include insoluble polymers, dispersible polymers and soluble polymers, all with reference to their solubility in aqueous media. For purposes of the following discussion, both dispersible and insoluble polymers are meant to refer to polymers that are crosslinked to the extent that makes them insoluble in aqueous media. Soluble polymers are either not crosslinked or crosslinked to such a minor extent that they are entirely soluble in aqueous media. Thus, dispersible polymers are herein considered to have such limited solubility as to he essentially insoluble, despite the fact that, although they do not dramatically precipitate from solution, they may appear to he soluble. Such dispersible polymers reflect their insolubility by being capable of being separated from aqueous media by methods such as centrifugation or filtration.
Robinson, in U.S. Pat. No. 4,615,697 describes a controlled release treatment composition including a bioadhesive and an effective amount of treating agent, the bioadhesive comprising a water swellable, but insoluble, fibrous, i.e., particulate, crosslinked carboxy functional polymer.
U.S. Pat. No. 2,798,053 describes, for carboxyvinyl polymers, useful crosslinking agents that are not free of polyalkenyl polyethers, such as polyallyl sucrose or polyallylpentaerythritol containing an average of about three allyl groups per molecule, as in CARBOPOL 934.
The bioadhesives of U.S. Pat. No. 4,615,697 are water insoluble, in that they separate from the aqueous solution in which they are prepared. U.S. Pat. No. 3,074,852, U.S. Pat. No. 3,330,729 and U.S. Pat. No. 4,226,848 describe bioadhesives that contain water dispersible polymers having CARBOPOL 934, a polymer of acrylic acid that is crosslinked with polyallyl sucrose, the polymers being minimally crosslinked to so as to become sufficiently xe2x80x9cwater solublexe2x80x9d to provide a measurable viscosity at 0.2 weight % in water. However, it is apparent from its very limited solubility, that CARBOPOL 934 is considered to be water dispersible rather than water soluble.
Most recently, Robinson in U.S. Pat. No. 5,474,768 added to the formulation described in U.S. Pat. No. 4,615,697 a water dispersible, viscosity enhancing, agent consisting of a nonionic or anionic polymer, the anionic polymer having, for example, a plurality of carboxyl groups.
Potts et al, in U.S. Pat. No. 4,188,168 describes an aqueous topically administered ophthalmic composition, having a pH less than 5, containing N-(5-sulphamoyl-1,3,4-thiadiazol-2-yl)acetamide, otherwise known as acetolazolamide, and either: a) a preformed aqueous gel, or b) an aqueous gel-forming polymer capable of forming gel in-situ when applied topically. The in-situ gel is a xe2x80x9cthermal gelxe2x80x9d which is liquid at room temperature and gels at body temperature, having a sol-gel transition between 25-40xc2x0 C. Examples are Pluronic or Tetronic polyoxyethylene polyoxypropylene copolymers, as are described in U.S. Pat. No. 4,188,373.
Chandrasekaran in WO 89/06964 describes a topical ophthalmic medicament delivery system, rapidly gellable on contact with the eye""s tear fluid, containing: an aqueous suspension, of pH 3-6.5, osmotic pressure 10-400 mOsM, and viscosity 1000-30,000 cp, containing 0.1-6.5% of a lightly crosslinked carboxyl containing polymer that has a particle size  less than 50 xcexcm in equivalent spherical diameter.
Chang, in U.S. Pat. No. 5,292,517 describes a reversible gelling, erodable drug delivery composition that exhibits a change in solution viscosity in response to changes in pH. The composition contains an aqueous solution from 1-25% w/v At the polymer poly(methylvinylether/maleic acid) having a number average molecular weight from 20.000-100.000: and 0.005-50% w/v of a therapeutic or diagnostic pharmaceutical compound that is stable in the presence of the polymer. Exposure to higher physiological pH, as in the eve. causes the polymer to deprotonate and thereby unwind its polymeric chain. The polymeric chain, now occupying increased polymeric volume, has increased resistance to flow: thereby adhering to the tissue and providing sufficient time for the pharmaceutical compound to be biologically available.
U.S. Pat. No. 5,393,798 describes a hydrogel material comprised of copolymers of poly(alkylvinylether/maleic acid), containing a modifying group R selected from the group consisting of xe2x80x94NHxe2x80x94(CH2)1-5xe2x80x94CHxe2x95x90CH2 and xe2x80x94NHxe2x80x94COxe2x80x94NHxe2x80x94CH2CHxe2x95x90CH2, where the modifying group is substituted for one of the hydroxyl groups of a maleic acid moiety.
Previous products that employ polycarboxyl groups containing polymers attempt to achieve adhesion of the formulations to biomembranes and to prevent them from leaking from or washing off the biomembranes, depending for bioadhesion on hydrogen bonding of the carboxyl groups to the biomembranes, the source of the carboxyl groups being water insoluble, albeit water swellable polymers. Although crosslinking prevents the polymer from washing off or leaking from the biomembrane, it limits to a significant degree the availability of the hydrogen bonds of the carboxyl groups to interact with the carboxyl groups present on the biomembrane.
Therefore, it is an object of this invention to provide spreadable lubricious compositions, buffered to a bioacceptable pH, and having a pseudoplastic elastic modulus profile, the compositions being adhesive to biomembranes such as oral, vaginal and ophthalmic mucosa.
It is a further object of this invention to provide such spreadable lubricious compositions that also contain and provide moisture to the biomembranes, do not readily flow off, or leak from, the biomembranes, and are not readily removed or washed from the biomembranes.
It is yet another object of this invention to provide spreadable lubricious compositions that require much lower amounts of polyhydroxy compound when compared with known formulations, and yet provide enhanced lubricity.
It is still a further object of this invention to describe methods for making such compositions.
It is yet still a further object of this invention to describe methods of use of such compositions.